Magnetic resonance imaging (MRI) has become a widely used tool for medical imaging and research. As a medical imaging technique, MRI is preferred by patients as it does not require exposure to ionizing radiation. Further, MRI has proven to be the best way to obtain images of soft tissues in the body. Because MRI can be used for imaging soft tissues, it can be effectively used to determine if a tumor or other lesion has developed in an organ and to determine structural changes in the brain, along with a multitude of other uses.
Very briefly, MRI requires placing the patient to be imaged in a strong magnetic field. The magnetic field causes the hydrogen nuclei to align so that they are spinning either parallel or antiparallel to the magnetic field. A radiofrequency (RF) pulse is then applied that excites the spinning hydrogen nuclei out of alignment. After application of the RF pulse, the excited nuclei relax back to alignment with the magnetic field, emitting RF signals that are detected by the MRI apparatus. Detection of the RF signals is used to calculate both the longitudinal relaxation time (T1) and transverse relaxation time (T2), which are used to form images of the patient.
The primary limitation of MRI is its sensitivity. Contrast agents are often administered to the patient before imaging overcome sensitivity limitations. These contrast agents cause changes in T1 and T2 for surrounding hydrogen nuclei, which helps clearly differentiate structures in the MRI image.
One class of contrast agents is the positive contrast agents, which decrease T1 and T2 to a similar extent and are typically used in obtaining T1 weighted images. Positive contrast agents cause a tissue structure associated with the contrast agent to appear brighter on an MRI image, making these agents very useful for increasing MRI specificity.
A majority of the positive contrast agents approved by the Food and Drug Administration (FDA) contain the paramagnetic metal ion gadolinium. Although free Gd3+ is toxic, it can be ligand protected to greatly reduce its bioavailability. While Gd containing contrast agents are generally considered safe for administration to humans, recently concerns have arisen due to the possible causal connection between Gd contrast agents and the formation of nephrogenic systemic fibrosis in patients with renal dysfunction. Because of this, physicians are now debating the risks of administering Gd contrast agents to certain types of patients, and the FDA has requested the manufacturers of Gd contrast agents to add new warning information to their labels (H. Steen and V. Schwenger, Pediatr Nephrol, 2007, 22, 1239; www.fda.gov/cder/drug/infopage/gcca/qa_200705.htm).
There is also an environmental concern with the use of Gd contrast agents, as their impact on the environment after excretion by the patient is largely unknown. As the popularity of MRI continues to increase, more and more Gd contrast agents will be used, meaning that more Gd will be released into the environment.
Because of the possible health and environmental concerns related to the use of Gd contrast agents, it is desirable to develop contrast agents using metals that are better tolerated both by the body and the environment. One metal that has paramagnetic properties making it suitable for use as an MRI contrast agent while also being more benign to health and the environment is manganese. However, the toxicity of free Mn metal has limited the development of Mn contrast agents (A Koretsky and A Silva, NMR in Biomedicine, 2004, 17, 527). A Mn contrast agent, manganese dipyrodoxaldiphosphate (Mn-DPDP), has been approved by the FDA as safe for human use and is sold by GE Healthcare under the name Teslascan™. However, Mn-DPDP has only been approved for imaging of the liver and has shown only limited effect on T1 and T2 in tissues outside of liver and kidney (G. Elizondo et al., Radiology, 1991, 178, 73).
U.S. Pat. Nos. 5,330,742 and 5,548,870 to Deutsch et al., describe paramagnetic metal cluster compounds for enhancing MRI. However, the reduced metal cluster described, Z+[Mn12X12(OYR)16(L)4], is highly reactive and has not been demonstrated to be stable in biological systems because it would react immediately in water. Also, as this cluster is insoluble in water, it must be conjugated to a carrier in order to be delivered as a contrast agent. Although the patents describe conjugating this reactive cluster to polymeric or microspheric carriers, liposome carries and hydroxyapatite carriers, these carriers only provide for limited increases in the solubility of the cluster. Further, the conjugation of the Z+[Mn12X12(OYR)16(L)4] cluster is unlikely to make it more suitable for use in a biological system.
U.S. Pat. No. 5,364,953 to Beaty et al. describes paramagnetic metal clusters having oxygen and/or nitrogen containing ligands for use as MRI contrast agents. However, the metal clusters taught in the patent are not more than sparingly soluble in water and precipitate from solution over time.
As such, there remains a need in the art for a highly water soluble and bio-stable contrast agent that provides high specificity while also being benign to the body and the environment.